Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]([CH3:22])=[CH:20][C:6]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]2=[O:19])=[C:5]([F:23])[CH:4]=1.C(N(C(C)C)C(C)C)C.Cl[C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][N:35]=1.O>CS(C)=O>[Br:2][C:3]1[C:21]([CH3:22])=[CH:20][C:6]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][N:35]=4)[CH2:15][CH2:14]3)[C:9]2=[O:19])=[C:5]([F:23])[CH:4]=1
Reactant: Cc1cc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1Br
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(Br)cc4F)C3=O)CC2)nc1
Temperature: 110 °C
Yield: 59.9 %

Procedure:
(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 1.47 mmol) was dissolved in DMSO (10 mL) and N-ethyl-N-isopropylpropan-2-amine (641 μl, 3.68 mmol) and 2-chloro-5-ethylpyrimidine (252 mg, 1.77 mmol) were added and the reaction heated to 110° C. overnight. The reaction was cooled to ambient temperature, poured into water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (60% EtOAc in hexanes) to afford (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (420 mg, 0.880 mmol, 59.8% yield) as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1.C(O)(=O)C.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[NH:20][C:12]2[CH:11]=[C:10]([C:9](=[O:23])[NH:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[N:16]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2[nH]1
Yield: 67.3 %

Procedure:
Five-percent palladium on carbon (0.10 g) was added to a mixture of 1.00 g of crude N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide, 8 ml of acetic acid and 12 ml of ethanol, and the solution was stirred in a hydrogen atmosphere at 80° C. for 7 hours. The solid material was separated through filtration, and the filtrate was concentrated. Ethyl acetate was added to the residue for crystallization. The crystals were separated through filtration, and were dried to give 0.57 g of 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (252).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1>>[O:9]=[C:7]1[N:24]2[CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=[CH:20][C:19]2=[N:1][C:2]2[S:3][C:4]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 6.2 %

Procedure:
From 5.0 g (0.02 mol) of 2-amino-5-phenyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and 3.2 g (0.02 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), following the procedure of Example 3, there is obtained 0.4 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 387°-392° C. after recrystallization from pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.NN.FC1C=CC(NO)=CC=1.[CH3:22][N:23]=[C:24]=[O:25]>O1CCCC1.[Pd]>[CH3:22][NH:23][C:24]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:10])=[O:25]
Reactant: CN=C=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pd]
Agent: NN
Agent: ONc1ccc(F)cc1
Solvent: C1CCOC1
Product: CNC(=O)N(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
p-Fluoronitrobenzene (14.1 g; 0.1 mole) was dissolved in tetrahydrofuran (100 ml.). Ten percent palladium on charcoal catalyst (0.1 g.) was added to the solution followed by hydrazine (6.0 ml; 0.105 mole), and the resulting mixture stirred at room temperature for about 48 hours with cooling as necessary. The reaction mixture containing N-(4-fluorophenyl) hydroxylamine was dried over anhydrous magnesium sulfate and filtered. To this solution was added methyl isocyanate (6.2 ml; 0.1 mole) and the mixture stirred for about 15 minutes. The reaction mixture was concentrated by distilling and then washed with hexane and filtered to yield 1-methyl-3-(4'-fluorophenyl)-3-hydroxyurea as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](=O)(O[C@H]1CCOC1)[O:40]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C@H:34]1[CH2:36][CH2:39][O:40][CH2:35]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was dissolved in a 1:1 solution of CH2Cl2/TFA (1 mL) and allowed to stir at room temperature for 1 hour. The solution was then extracted into ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated to a clear oil. The resulting oil was then dissolved in THF (1 mL) and combined with 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl] carbonate (0.05 mmol, 13 mg) DIEA (0.08 mmol, 14 μL) and allowed to stir for 15 hours. The reaction was neutralized by the addition of acetic acid and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate), providing 19 mg (37%) of a white solid. H1-NMR (CDCl3): δ 7.70 (2H,d), 7.29-7.17 (6H,m), 6.97 (2H,d), 5.1 (1H,s), 4.76 (1H,d), 4.17 (1H,m), 3.86 (3H,s), 3.87-3.70 (6H,m), 3.68-3.60 (1H,m), 3.06 (1H,bs), 2.89 (2H,m), 2.02 (3H,m), 1.89 (1H,m), 1.71 (2H,m), 1.28-1.08 (6H,m); MS (ESI): M+Na=585.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]([O:18][CH3:19])=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]([O:18][CH3:19])=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]2)[CH:11]=1
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(N2CCN(C(C)=O)CC2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Acetyl chloride (0.10 ml) was mixed with a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (370 mg) and triethylamine (0.32 mL) in methylene chloride (8 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and, after filtering off the insoluble portion, was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (338 mg) as colorless crystals (81%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(O)ncc(C(=O)O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Temperature: 0 °C
Yield: 86 %

Procedure:
A stirred solution of 1-hydroxy-5-methylisoquinolin-4-carboxylic acid (Intermediate-9) (600 mg, 3 mmol) in POCl3 (10 mL) was heated to 100° C. for 40-50 min. The reaction mixture was poured into ice-water, extracted with CH2Cl2 (2×100 mL), washed with water (2×100 mL), dried over Na2SO4, filtered and evaporated to give the desired compound (550 mg, 86%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=N[NH:26]2.[CH3:31]COCC>COCCOCCOC>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:2]3[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:31]1
Reactant: Oc1cccc2[nH]ncc12
Reactant: CCOCC
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]ccc12

Procedure:
Methyl 2,4-difluorobenzoate (2 g, 11.6 mmol)), K3PO4 (2.4 g, 11.3 mmol) and 4-hydroxyindazole (1.40 g, 10.5 mmol) were stirred at 115° C. in diglyme (20 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, followed by brine, and then dried over Na2SO4 and filtered. The filtrate was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1>ClCCl>[S:8]([O:27][CH2:26][CH2:25][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:10])(=[O:9])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cccc(CCO)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Temperature: -10 °C

Procedure:
In a 250-cm3 flask, 4 g of 2-(7-methoxy-1-naphthyl)ethanol are dissolved in 100 cm3 of dichloromethane, and 3.3 cm3 of triethylamine are added. The mixture is cooled in an ice bath at -10° C. and 2.75 g of mesyl chloride are then added dropwise and with stirring. The mixture is left stirring for 30 minutes. The aqueous phase is extracted with 3 times 50 cm3 of dichloromethane, and the organic phase is washed with 3 times 20 cm3 of 1N hydrochloric acid solution and then with water, dried over potassium carbonate and evaporated. The oily residue is recrystallized.
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[S:9]([Cl:12])(Cl)=[O:10].[OH2:13]>>[Cl:8][C:3]1[C:2]([S:9]([Cl:12])(=[O:10])=[O:13])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=S(Cl)Cl
Reactant: O
Product: O=S(=O)(Cl)c1cccnc1Cl

Procedure:
reaction of the diazonium salt of 3-amino-2-chloropyridine with a mixture of thionyl chloride in water, in the presence of an electron transfer catalyst, to give 2-chloropyridine-3-sulfonyl chloride;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a cooled, stirred solution of 5-bromopyridine-2-carbaldehyde (3.72 g, CAS 31181-90-5) and (trifluoromethyl)trimethylsilane (3.56 ml) in THF (30 ml) at 0° C. was added dropwise tetrabutylammonium fluoride solution (1.0 ml, 1 M solution in THF). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 hours. The mixture was then diluted with 1 N aq. HCl (20 ml) and stirring was continued for a further 2 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanol as a light yellow solid (3.35 g, 65%). MS (ISP): 258.0 ([{81Br}M+H]+), 256.1 ([{79Br}M+H]+).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[I:18]CI.N(OCCC(C)C)=O>CC#N>[I:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17]
Reactant: ICI
Reactant: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1ccc(-n2nc(C)c(C#N)c2I)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.30 g, 5.70 mmol) in MeCN (8 mL) was added diiodomethane (1.93 mL, 23.9 mmol) followed by isoamyl nitrite (0.19 mL, 1.42 mmol). The reaction vessel was heated using a heating gun to initiate the reaction. After the rest of isoamyl nitrite (1.72 mL, 12.8 mmol) was added and the reaction was stirred for 1 hour at 50° C. The reaction was concentrated into silica and purified using silica gel (Heptane-CH2Cl21:0 to 0:1) gave 5-iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.45 g, 75%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1)=[O:4].N1C=CN=C1.[Si:25](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[Si:25]([O:17][C@H:9]1[C:10]2[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:7][CH2:8]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N[C@@H]1CC[C@@H](O)c2ccc(F)cc21)C(F)(F)F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-N-((1R,4R)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (2.71 g, 9.78 mmol, 1 equiv) and imidazole (1.33 g, 19.56 mmol, 2 equiv) were dissolved in anhydrous DMF (40 mL) and cooled in ice bath. Tert-Butyldiphenylsilyl chloride (3.25 mL, 12.71, 1.3 equiv) was added dropwise. The reaction solution was stirred at RT for 16 h. The DMF was removed by evaporation. The residue was dissolved in EtOAc (200 mL) and washed with water, brine and dried (Na2SO4). The organic phase was evaporated to dryness to give an oil residue, which was purified by ISCO (40 g column, EtOAc-hexane 10-50%) to give a white solid product (2.16 g, TLC: pure) and a mixture (3.0 g). 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.26-7.30 (q, 1H), 7.09 (m, 1H), 6.98 (dd, 1H), 5.07-5.14 (m, 1H), 4.77-4.80 (m, 1H), 2.06-2.15 (m, 1H), 1.74-1.92 (m, 2H), 1.56-1.669 m, 1H), 1.03 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc2cc[nH]c2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-hydroxymethyl indole (4.9 g, 33.3 mmol) in dry dichloromethane (200 ml) was added a solution of pyridinium dichromate (15.97 g, 42.5 mmol) in dry dichloromethane (100 ml) and the suspension stirred at room temperature for 5 hours. The suspension was diluted with diethyl ether and filtered through a pad of silica to give an orange solution, which was evaporated in vacuo. The crude solid was purified by flash chromatography on silica, eluting with 50% diethyl ether in hexane, to yield a pale orange solid. Recrystallisation from diethyl ether/40°-60° C. petrol gave a pale orange crystalline solid, m.p. 126°-128° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cccc3cnccc23)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2cccc3cnccc23)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-isoquinolin-5-yl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=2[Cl:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:32]=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:32])=[O:24])=[CH:21][C:20]=2[Cl:28])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoic acid (0.5 g, 1.03 mmol) was taken up in THF (10 ml). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.22 g, 1.24 mmol) and N-methyl morpholine (0.34 ml, 3.09 mmol) were added. The mixture stirred at room temperature for 1 hour. At this time, NH4OH (2.5 ml) was added and the reaction stirred at room temperature for one more hour. To the reaction mixture was added more THF (50 ml) and water (200 ml). The mixture was extracted with ethyl acetate. The ethyl acetate extraction was washed with saturated brine solution. The brine layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to yield a white powder (0.38 g, 76%) 1H NMR (300 MHz, CD3OD) δ 8.18 (d, J=1.81 Hz, 1H), 8.02 (dd, J=8.26, 2.01 Hz, 1H), 7.69 (app q, J=8.26 Hz, 1H), 7.55 (d, J=8.06 Hz, 1H) 7.12-7.06 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.07 (s, 3H). ES MS m/z 482 (M+H). ES-HRMS m/z 482.9919 (M+H calcd for C20H15BrClF2N2O3 requires 482.9917).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH:7]([C:11]1[N:12]=[C:13]([NH:16][CH:17]=[O:18])[S:14][CH:15]=1)[C:8]([OH:10])=O.[CH3:19][N:20]1[C:24]([S:25][CH2:26][C:27]2[CH2:28][S:29][C@@H:30]3[CH:37]([NH2:38])[C:36](=[O:39])[N:31]3[C:32]=2[C:33]([OH:35])=[O:34])=[N:23][N:22]=[N:21]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:19][N:20]1[C:24]([S:25][CH2:26][C:27]2[CH2:28][S:29][C@@H:30]3[CH:37]([NH:38][C:8](=[O:10])[CH:7]([OH:6])[C:11]4[N:12]=[C:13]([NH:16][CH:17]=[O:18])[S:14][CH:15]=4)[C:36](=[O:39])[N:31]3[C:32]=2[C:33]([OH:35])=[O:34])=[N:23][N:22]=[N:21]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(O)C(=O)O)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=CN=c1[nH]c(C(O)C(=O)O)cs1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3csc(NC=O)n3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To dimethylformamide (5 ml.) was dropwise added phosphorus oxychloride (0.794 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C., and then cooled to -20° C. To the mixture was gradually added 2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (0.505 g.) at -20° C., and the mixture was stirred for 45 minutes at -12° to -10° C. Thus obtained mixture was added to a solution, which was prepared by stirring a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (0.804 g.), bis(trimethylsilyl)acetamide (2.62 ml.) in methylene chloride (15 ml.) for an hour at room temperature and for 2 hours at 35° to 40° C. and then by cooling it to -30° C., at a time. The mixture was stirred for an hour at -20° to -15° C., and then methylene chloride was distilled off. The resulting residue was purified by a conventional manner to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-formylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.51 g.).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C@@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([F:33])([F:32])[C:29](O)=[O:30])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[NH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([F:33])([F:32])[C:29]([N:18]2[CH2:19][CH2:20][N:13]3[C@H:14]([CH2:15][O:16][C@@H:11]([C:5]4[C:6]([CH3:10])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=4)[C:8]#[N:9])[CH2:12]3)[CH2:17]2)=[O:30])=[CH:26][N:27]=1
Reactant: Nc1ncc(C(F)(F)C(=O)O)cn1
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@H]2CN3CCN(C(=O)C(F)(F)c4cnc(N)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-fluoro-2-methyl-3-((3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile (60 mg, 0.218 mmol) and 2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetic acid (60.3 mg, 0.218 mmol) in anhydrous DMF (2724 μL) was added DIEA (133 μL, 0.763 mmol) followed by HATU (149 mg, 0.392 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and purified on mass-directed preparative HPLC, Polar method (Column: Sunfire Prep C18, OBD 5 um, 30×100 mm). LC/MS: [(M+1)]+=447.08; 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 2H), 8.11-8.17 (m, 1H), 7.30-7.39 (m, 3H), 4.83-4.92 (m, 1H), 4.07-4.27 (m, 1H), 3.43-3.76 (m, 2H), 3.00-3.37 (m, 4H), 2.72-2.96 (m, 2H), 2.58-2.68 (m, 1H), 2.16-2.55 (m, 4H).